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BIOC 460 DR. TISCHLER LECTURE 37 REGULATION OF ACETYL CoA PROCESSING OBJECTIVES 1. Regulation of processes in the formation of acetyl CoA: a) describe regulation of hormone-sensitive lipase by covalent modification b) mechanism by which activators or inhibitors of phosphodiesterase affect activity of hormone-sensitive lipase 2. Regulation of processes in the utilization of acetyl CoA: a) factors that induce (increase) or repress (decrease) synthesis of acetyl CoA carboxylase and FAS b) events associated with polymerization-depolymerization describe of acetyl CoA carboxylase c) events associated with covalent modification of acetyl CoA carboxylase d) induction of HMG CoA reductase through mRNA production in the presence of low cholesterol. e) events associated with covalent modification of HMG-CoA reductase 3. Drugs that inhibit HMG-CoA reductase to lower cholesterol LIPOLYSIS Mobilization of fats from triacylglycerols Regulated step – hormone sensitive lipase Specific for removing first fatty acid Phosphorylated “a” form is active Dephosphorylated “b” form is inactive cell membrane HORMONES Epinephrine Glucagon ATP Adenylyl cyclase RECEPTORS += - = activation inhibition cyclic AMP Triacylglycerol ADP Fatty acid + Diacylglycerol HSL-a OP Insulin + protein inactive active kinase A PhosphoATP diesterase caffeine - theophylline AMP + insulin HSL-b + protein phosphatase OH Pi (inactive form) Figure 1. Hormonal activation of triacylglycerol (hormone-sensitive) lipase. Hormone signals from epinephrine or glucagon promote mobilization of fatty acids (lipolysis) via production of cyclic AMP. Activated protein kinase A, phosphorylates HSL-b to the active HSL-a form . Table 1. Long-term control by induction or repression of acetyl CoA carboxylase and fatty acid synthase PHYSIOLOGICAL CONDITION EFFECT High-carbohydrate, low-fat diet synthesis High-fat diet synthesis Fasting synthesis acetyl CoA carboxylase polymeric ATP + HCO3ADP + Pi malonyl CoA acetyl CoA ACTIVE FORM palmitoyl-CoA promotes depolymerization LOW ACTIVITY acetyl CoA carboxylase (monomeric) citrate promotes polymerization OH Figure 2a. Regulation of acetyl CoA carboxylase by citrate and palmitoyl CoA via polymerization and depolymerization acetyl CoA carboxylase polymeric ATP + HCO3ADP + Pi malonyl CoA acetyl CoA ACTIVE FORM palmitoyl-CoA promotes depolymerization LOW ACTIVITY acetyl CoA carboxylase (monomeric) citrate promotes polymerization OH Figure 2a. Regulation of acetyl CoA carboxylase by citrate and palmitoyl CoA via polymerization and depolymerization LOW ACTIVITY acetyl CoA carboxylase (monomeric) OH OPO3 ADP ATP INACTIVE FORM AMP PK (active) OPO3 OPO3 ADP kin. kinase (active) ADP protein kinase A (cyclic AMP-activated) via ATP cAMP glucagon or epinephrine kin. kinase (inactive) ATP AMP PK (inactive) OH Figure 2b. Regulation of acetyl CoA carboxylase by glucagon, epinephrine and insulin OH protein phosphatase +insulin Pi LOW ACTIVITY acetyl CoA carboxylase (monomeric) OH OPO3 ADP ATP OPO3 AMP protein kinase (active) ADP ADP via cAMP glucagon or epinephrine ATP ATP AMP protein kinase (inactive) protein phosphatase Pi kinase kinase (inactive) OPO3 protein phosphatase Pi kinase kinase (active) protein kinase A (cyclic AMP-activated) INACTIVE FORM OH Reversing the inactivation of acetyl CoA carboxylase OH protein phosphatase +insulin Pi LOW ACTIVITY acetyl CoA carboxylase (monomeric) OH OPO3 ADP ATP OPO3 AMP protein kinase (active) ADP ADP via cAMP glucagon or epinephrine ATP ATP AMP protein kinase (inactive) protein phosphatase Pi kinase kinase (inactive) OPO3 protein phosphatase Pi kinase kinase (active) protein kinase A (cyclic AMP-activated) INACTIVE FORM OH Reversing the inactivation of acetyl CoA carboxylase OH ENDOPLASMIC RETICULUM High Cholesterol NUCLEUS = SREBP, sterol regulatory element binding protein ENDOPLASMIC RETICULUM Low Cholesterol NUCLEUS synthesis of HMG CoA reductase mRNA for HMG CoA Reductase Figure 3. HMG CoA reductase is induced when intracellular cholesterol becomes too low while with high cholesterol SREBP is bound to the endoplasmic reticulum and is thus rendered ineffective mevalonate + 2 NADP+ + CoA Figure 4. Inactivation of HMG CoA reductase by phosphorylation in response to glucagon or epinephrine INACTIVE FORM HR OH ACTIVE FORM HMG-CoA +2 NADPH +2 H+ OPO3 HR ADP ATP RK (active) OPO3 ADP RKK(active) ADP ATP RK (inactive) PKA + via cAMP ATP glucagon or epinephrine OPO3 RKK (inactive) OH OH mevalonate + 2 NADP+ + CoA Figure 4. Activation of HMG CoA reductase by dephosphorylation in response to insulin insulin + Pi INACTIVE FORM PP HR HR OH ATP ACTIVE HMG-CoA +2 NADPH FORM +2 ADP OPO3 RK (active) H+ OPO3 PP ADP RKK (active) ADP + RK (inactive) OH PKA + ATP via cAMP glucagon or epinephrine insulin Pi ATP OPO3 PP + insulin Pi RKK (inactive) OH mevalonate + 2 NADP+ + CoA Figure 4. Activation of HMG CoA reductase by dephosphorylation in response to insulin insulin + Pi INACTIVE FORM PP HR HR OH ATP ACTIVE HMG-CoA +2 NADPH FORM +2 ADP OPO3 RK (active) H+ OPO3 PP ADP RKK (active) ADP + RK (inactive) OH PKA + ATP via cAMP glucagon or epinephrine insulin Pi ATP OPO3 PP + insulin Pi RKK (inactive) OH
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